Task-related fMRI BOLD response to hyperinsulinemia in healthy older adults.

BACKGROUND: There is growing evidence to suggest that the brain is an important target for insulin action, and that states of insulin resistance may extend to the CNS with detrimental effects on cognitive functioning. Although the effect of systemic insulin resistance on peripheral organs is well-studied, the degree to which insulin impacts brain function in vivo remains unclear. METHODS: This randomized, single-blinded, 2-way-crossover, sham-controlled, pilot study determined the effects of hyperinsulinemia on fMRI brain activation during a 2-back working memory task in 9 healthy older adults (aged 57-79 years). Each participant underwent two clamp procedures (an insulin infusion and a saline placebo infusion, with normoglycemia maintained during both conditions), to examine the effects of hyperinsulinemia on task performance and associated blood-oxygen-level dependent (BOLD) signal using fMRI. RESULTS: Hyperinsulinemia (compared to saline control) was associated with an increase in both the spatial extent and relative strength of task-related BOLD signal during the 2-back task. Further, the degree of increased task-related activation in select brain regions correlated with greater systemic insulin sensitivity, as well as decreased reaction times and performance accuracy between experimental conditions. CONCLUSION: Together, these findings provide evidence of insulin action in the CNS among older adults during periods of sustained cognitive demand, with the greatest effects noted for individuals with highest systemic insulin sensitivity. FUNDING: This work was funded by the National Institutes of Health (5R21AG051958, 2016).

The technical reliability and biotemporal stability of cerebrospinal fluid biomarkers for profiling multiple pathophysiologies in Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is a complex neurodegenerative disease driven by multiple interacting pathophysiological processes that ultimately results in synaptic loss, neuronal death, and dementia. We implemented a fit-for-purpose modeled approach to qualify a broad selection of commercially available immunoassays and evaluate the biotemporal stability of analytes across five pathophysiological domains of interest in AD, including core amyloid-ß (Aß) and tau AD biomarkers, neurodegeneration, inflammation/immune modulation, neurovascular injury, and metabolism/oxidative stress. METHODS: Paired baseline and eight-week CSFs from twenty participants in a clinical drug trial for mild cognitive impairment (MCI) or mild dementia due to AD were used to evaluate sensitivity, intra-assay precision, inter-assay replicability, and eight-week biotemporal stability for sixty unique analytes measured with commercially available single- and multi-plex ELISA assays. Coefficients of variation (CV) were calculated, and intraclass correlation and Wilcoxon signed rank tests were applied. RESULTS: We identified 32 biomarker candidates with good to excellent performance characteristics according to assay technical performance and CSF analyte biotemporal stability cut-off criteria. These included: 1) the core AD biomarkers Aß1-42, Aß1-40, Aß1-38, and total tau; 2) non-Aß, non-tau neurodegeneration markers NfL and FABP3; 3) inflammation/immune modulation markers IL-6, IL-7, IL-8, IL-12/23p40, IL-15, IL-16, MCP-1, MDC, MIP-1ß, and YKL-40; 4) neurovascular markers Flt-1, ICAM-1, MMP-1, MMP-2, MMP-3, MMP-10, PlGF, VCAM-1, VEGF, VEGF-C, and VEGF-D; and 5) metabolism/oxidative stress markers 24-OHC, adiponectin, leptin, soluble insulin receptor, and 8-OHdG. CONCLUSIONS: Assays for these CSF analytes demonstrate consistent sensitivity, reliability, and biotemporally stability for use in a multiple pathophysiological CSF biomarker panel to profile AD. Their qualification enables further investigation for use in AD diagnosis, staging and progression, disease mechanism profiling, and clinical trials.

Physician preference items: what factors matter to surgeons? Does the vendor matter?

BACKGROUND: The USA devotes roughly $200 billion (6%) of annual national health expenditures to medical devices. A substantial proportion of this spending occurs during orthopedic (eg, hip and knee) arthroplasties - two high-volume hospital procedures. The implants used in these procedures are commonly known as physician preference items (PPIs), reflecting the physician's choice of implant and vendor used. The foundations for this preference are not entirely clear. This study examines what implant and vendor characteristics, as evaluated by orthopedic surgeons, are associated with their preference. It also examines other factors (eg, financial relationships and vendor tenure) that may contribute to implant preference. METHODS: We surveyed all practicing orthopedic surgeons performing 12 or more implant procedures annually in the Commonwealth of Pennsylvania. The survey identified each surgeon's preferred hip/knee vendor as well as the factors that surgeons state they use in selecting that primary vendor. We compared the surgeons' evaluation of multiple characteristics of implants and vendors using analysis of variance techniques, controlling for surgeon characteristics, hospital characteristics, and surgeon-vendor ties that might influence these evaluations. RESULTS: Physician's preference is heavily influenced by technology/implant factors and sales/service factors. Other considerations such as vendor reputation, financial relationships with the vendor, and implant cost seem less important. These findings hold regardless of implant type (hip vs knee) and specific vendor. CONCLUSION: Our results suggest that there is a great deal of consistency in the factors that surgeons state they use to evaluate PPIs such as hip and knee implants. The findings offer an empirically derived definition of PPIs that is consistent with the product and nonproduct strategies pursued by medical device companies. PPIs are products that surgeons rate favorably on the twin dimensions of technology and sales/service.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

Biomarkers in Alzheimer's, Frontotemporal, Lewy Body, and Vascular Dementias.

This article reviews the current evidence base for biomarkers of the most common causes of dementia in later life: Alzheimer's disease (AD), frontotemporal lobar degenerations, Lewy body dementias, and vascular cognitive impairment and dementia. Biomarkers are objectively measurable indicators of normal physiology, pathological processes, or response to an intervention. Ideally, they are sensitive, specific, easy to obtain, and closely reflect the underlying biological processes of interest. While such markers are well established and in broad clinical use for common disorders in general medicine (e.g., thallium stress tests for coronary artery disease or serum blood urea nitrogen and creatinine for renal failure), analogous, validated markers for AD or other common dementias are limited, although biomarkers in research settings and specialty dementia clinics are progressing toward clinical use. By way of introducing current and future biomarkers for dementias of later life, this article will benefit the practicing clinician by increasing awareness of the availability and utility of current and emerging biomarkers in dementia diagnosis and prognosis and for monitoring new disease-modifying therapeutics that arrive in the clinic over the coming decade.

Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study.

Epidemiological studies have identified a robust association between type II diabetes mellitus and Alzheimer disease (AD), and neurobiological studies have suggested the presence of central nervous system insulin resistance in individuals with AD. Given this association, we hypothesized that the central nervous system-penetrant insulin-sensitizing medication metformin would be beneficial as a disease-modifying and/or symptomatic therapy for AD, and conducted a placebo-controlled crossover study of its effects on cerebrospinal fluid (CSF), neuroimaging, and cognitive biomarkers. Twenty nondiabetic subjects with mild cognitive impairment or mild dementia due to AD were randomized to receive metformin then placebo for 8 weeks each or vice versa. CSF and neuroimaging (Arterial Spin Label MRI) data were collected for biomarker analyses, and cognitive testing was performed. Metformin was found to be safe, well-tolerated, and measureable in CSF at an average steady-state concentration of 95.6 ng/mL. Metformin was associated with improved executive functioning, and trends suggested improvement in learning/memory and attention. No significant changes in cerebral blood flow were observed, though post hoc completer analyses suggested an increase in orbitofrontal cerebral blood flow with metformin exposure. Further study of these findings is warranted.

Agitation and Irritability in Alzheimer's Disease: Evidenced-Based Treatments and the Black-Box Warning.

More than five million Americans suffer from Alzheimer's disease (AD), and this number is expected to triple by 2050. While impairments in cognition, particularly memory, are typically the defining features of the clinical syndrome, behavioral symptoms are extremely common, affecting up to 90% of patients. Behavioral symptoms in AD can be difficult to manage and may require a combination of non-pharmacological and pharmacological approaches. The latter is complicated by FDA "black-box warnings" for the medication classes most often used to target these symptoms, and currently there are initiatives in place to limit their use. In this review, we describe common behavioral symptoms of AD-with a particular focus on the challenging symptoms of "agitation" and "irritability"-and discuss evidence-based approaches to their management. Ultimately, multidimensional approaches must be tailored to the patient and their environment, though evidence-based practices should define the treatment of agitation and irritability in AD.

Neuropsychological functioning in the acute and remitted States of late-life depression.

Late-life depression (LLD, major depression occurring in an adult 60 years or older) is a common condition that frequently presents with cognitive impairment. Up to half of individuals with LLD are estimated to have cognitive impairment greater than that of age- and education-matched comparators, with impairments of episodic memory, speed of information processing, executive functioning, and visuospatial ability being most common. To inform our understanding of the state- versus trait-effects of depression on neuropsychological functioning, and to overcome limitations of previous studies, we utilized baseline data from the longitudinal Pathways study to compare differences in single time point performance on a broad-based neuropsychological battery across three diagnostic groups of older adults, each comprised of unique participants (n = 438): currently depressed (n = 120), previously depressed but currently euthymic (n = 190), and never-depressed (n = 128). Consistent with our hypotheses, we found that participants with a history of depression (currently or previously depressed) performed significantly worse than never-depressed participants on most tests of global cognition, as well as on tests of episodic memory, attention and processing speed, verbal ability, and visuospatial ability; in general, differences were most pronounced within the domain of attention and processing speed. Contrary to our hypothesis, we did not observe differences in executive performance between the two depression groups, suggesting that certain aspects of executive functioning are "trait deficits" associated with LLD. These findings are in general agreement with the existing literature, and represent an enhancement in methodological rigor over previous studies given the cross-sectional approach that avoids practice effects on test performance.

Cognitive functioning and late-life depression.

This brief report provides an introduction to the topic of cognitive functioning in late-life depression (LLD). In addition to providing a review of the literature, we present a framework for understanding the heterogeneity of cognitive outcomes in this highly prevalent disorder. In addition, we discuss the relationship between LLD and dementia, and highlight the importance of regularly assessing cognitive functioning in older adults who present with depressive symptoms. If cognitive deficits are discovered during a neuropsychological assessment, we recommend referral to a geriatric psychiatrist or cognitive neurologist, for evaluation and treatment of the patient's symptoms.

Extreme nonresponse to acute phase cognitive therapy for depression: an attempt to replicate and extend.

As with other interventions for major depressive disorder (MDD), cognitive therapy (CT) results in treatment failure for about half of all participants. In 2007, Coffman and colleagues in Seattle studied this topic by identifying a group of patients who demonstrated an extremely poor response to CT (i.e., posttreatment BDI score≥31). They called these patients "extreme nonresponders" (ENR) and described the pretreatment characteristics that predicted response status. In the current study, we attempt a replication of the Seattle study with a larger sample of adults with recurrent MDD (N=473) who received a 16-20 session (12-14week) course of CT. The rate of ENR in this large sample was only 6.3% (30/473), compared to 22.2% (10/45) in the Seattle sample. Four pretreatment measures of symptom severity and functioning differed significantly among ENR and non-ENR participants. In each case, higher symptoms or poorer functioning were associated with ENR status. However, the combination of these factors in a regression model did not predict actual ENR status with the high degree of sensitivity or specificity observed in the Seattle study. These findings suggest that extreme nonresponse to CT is not as common as previously described and, although poor outcomes are associated with pretreatment clinical status, it is difficult to predict posttreatment symptom severity with a high degree of accuracy across different research samples.

Response to antidepressant medications in late-life depression across the spectrum of cognitive functioning.

OBJECTIVE: Late-life depression frequently co-occurs with cognitive impairment. To inform clinical management of these conditions, we examined the hypotheses that, relative to cognitively normal elders meeting DSM-IV criteria for major depressive disorder, those with cognitive impairment would require greater intensity of pharmacotherapy to reach criteria for antidepressant response and would take longer to respond. METHOD: Using data from the MTLD-3 study, we conducted a series of secondary analyses examining the implications of cognitive impairment for short-term, open-trial pharmacotherapy of late-life depression (major depressive disorder in individuals 65 years and older). The treatment algorithm consisted of 3 steps: initial treatment with a selective serotonin reuptake inhibitor (SSRI), a switch to a serotonin-norepinephrine reuptake inhibitor (SNRI) if the patient did not respond, and addition of an atypical antipsychotic if the patient did not respond to the SNRI. The first subject entered the protocol in April 2004, and the last subject exited in September 2009. We examined data for participants who completed the acute phase of MTLD-3 as responders and received a cognitive diagnosis (N = 153) based on National Alzheimer's Coordinating Center (NACC) Uniform Data Set criteria. We divided participants into 3 groups on the basis of NACC cognitive diagnosis: no cognitive disorder (n = 74), mild cognitive impairment (n = 60), and dementia (n = 19). For each group, we calculated the proportion of participants requiring first- (SSRI), second- (SNRI), or third-step (add-on atypical antipsychotic) treatment to meet criteria for response (17-Item Hamilton Depression Rating Scale score ≤ 10 for 3 consecutive weeks). We compared time to response across groups and correlates of nonresponse. RESULTS: The 3 groups did not differ in intensity of pharmacotherapy (P = .68) or time to response (P = .84). Nonresponse was more strongly correlated with longer major depressive episode duration (P = .0015), presence of recurrent depression (P = .002), and younger current age (P = .047), rather than cognitive status (P = .61). CONCLUSIONS: Cognitive status does not appear to impact short-term pharmacotherapy response variability in individuals whose depression responds to treatment with open-trial antidepressants delivered in a supportive, university-based medication clinic.

Cognition in Late Life Depression: Treatment Considerations.

Late life depression (LLD) frequently presents with cognitive impairment, and growing evidence suggests that these disease processes are "linked" in multiple ways. For some individuals, LLD may be a recurrence of a long-standing depressive illness, while for others it may be the leading symptom of a developing neuropathological disorder. Overall, studies investigating the relationship between treatment of LLD and improvement in cognitive functioning have yielded mixed results. Research suggests that a subset of individuals with LLD and cognitive dysfunction will experience an improvement in cognitive function after antidepressant treatment, though a significant proportion will continue to exhibit cognitive impairment following resolution of their depressive symptoms. From a treatment standpoint, it is critical to ensure that an individual's depressive symptoms have been treated to remission, measured by a standardized rating scale such as the Geriatric Depression Scale (GDS). SSRI or SNRI monotherapy is often effective, and may be enhanced by employing an evidence-based psychotherapy such as Problem Solving Therapy (PST) or Interpersonal Therapy (IPT), modified to accommodate cognitive impairments that may be present. With respect to specific treatment of cognitive dysfunction, cognitive augmentation or training strategies can be helpful for some patients, and may be explored in combination with treatment of the primary depressive episode. While the introduction of a cholinesterase inhibitor (e.g. donepezil) may be considered, the potential benefit (modest improvement in cognition and functioning) must be weighed against an increased risk for worsening or recurrent depression. Finally, lifestyle factors-such as aerobic exercise, follow-up with a primary care physician for management of co-morbid medical illnesses, and regular participation in stimulating activities (such as through a senior center)-are important and should be included as part of the overall treatment plan.

First-line pharmacotherapies for depression - what is the best choice?

Major depressive disorder is a significant public health problem and the leading cause of suicide worldwide. Since the discovery of the first effective medications for depression in the late 1950s, a variety of pharmacotherapies have been developed that are useful for treating the full range of depressive disorders. The availability of safer classes of antidepressants, as well as other factors, has resulted in a large increase in the number of depressed individuals who are treated for depression by their primary care providers. This review examines the antidepressants that are currently used as the initial or "first-line" therapies for major depressive disorder (MDD). These newer medications may be grouped into three classes: the selective serotonin reuptake inhibitors, the serotonin and norepinephrine reuptake inhibitors, and the norepinephrine-dopamine reuptake inhibitor. While the modern classes of antidepressants offer superior tolerability and safety over older medications such as the tricyclic antidepressants, there remains no universally effective pharmacologic treatment for MDD, and effective disease management requires careful attention to ongoing assessment of medication response and management of side effects.